Cocaine (COC) dependence in the United States is a major health problem that currently has no approved pharmacological therapies to help in treatment. The gold standard of rodent models used in addiction research is COC self-administration. We have used this model to show that extended exposure to COC results in a pharmacodynamic tolerance of the dopamine transporter (DAT). Tolerance of the DAT to COC is a relatively new phenomenon discovered by our lab, which opened up a new avenue of research into the manipulation of COC tolerance, which we will explore in this proposal. We found that administration of a single AMPH bolus (0.56 mg/kg IV) rapidly and completely reversed the COC tolerance at the DAT, and even caused COC potency to increase above control levels. The specific aims include experiments that characterize and expand on this discovery. In Specific Aim 1 we will explore the lowest effective dose of AMPH that can cause a reversal of DAT plasticity and the time course of this effect. Although this characterization is quite important, we are primarily interested in discovering the structural and functional changes in the DAT that are responsible for this effect. Thus, for Specific Aim 2, we will use structurally different DA releasers and blockers with different DAT affinities in place of an AMPH bolus and use slice voltammetry to explore COC potency and presynaptic DA function (release and uptake) in response to these compounds. Additionally, we are interested in the behavioral implications for our neurochemical data. In Specific Aim 3 we will test animals before and after self-administration and an AMPH bolus with locomotor assessments while another group will be assessed on a progressive ratio schedule of COC self-administration. While our interest is primarily in the basic pharmacology driving the DAT changes, this may be relevant to the literature proposing DAT releasers such as AMPH as putative COC addiction pharmacotherapies. Although agonist therapies for COC addiction are controversial, we may be able to define a putative mechanism for some of their therapeutic effects which could potentially drive more rationale design of such therapies.